Plasma Calcitonin Gene-related Peptide Concentration Research Articles

Evaluation of Plasma Calcitonin Gene-Related Peptide as a Biomarker for Painful Temporomandibular Disorder and Migraine.

To assess associations of plasma calcitonin gene-related peptide (CGRP) with chronic temporomandibular disorder (TMD) myalgia/arthralgia or frequent/chronic migraine, alone and in combination, and to evaluate relations between the CGRP concentration and clinical, psychological, and somatosensory characteristics of participants. The cross-sectional study selected four groups of adult volunteers: healthy controls (HCs), TMD without migraine, migraine without TMD, and TMD with migraine. Each group comprised 20 participants, providing 94% power to detect statistically significant associations with CGRP concentration for either TMD or migraine. TMD and headache were classified according to the Diagnostic Criteria for TMD and the International Classification for Headache Disorders, 3rd edition, respectively. Plasma CGRP was quantified with a validated high-sensitivity electrochemiluminescent Meso Scale Discovery assay. Questionnaires and clinical examinations were used to evaluate characteristics of TMD, headache, psychological distress, and pressure pain sensitivity. Univariate regression models quantified associations of the CGRP concentration with TMD, migraine, and their interaction. Univariate associations of the CGRP concentration with clinical, psychological, and pressure pain characteristics were also assessed. Among 80 participants enrolled, neither TMD nor migraine was associated with plasma CGRP concentration (P = 0.761 and P = 0.972, respectively). The CGRP concentration (mean ± SD) was similar in all 4 groups: HCs 2.0 ± 0.7 pg/mL, TMD 2.1 ± 0.8 pg/mL, migraine 2.1 ± 0.9 pg/mL, and TMD with migraine 2.2 ± 0.7 pg/mL. CGRP concentration was positively associated with age (P = 0.034) and marginally with body mass index (P = 0.080) but was unrelated to other participant characteristics. In this well-powered study, interictal plasma concentration of CGRP was a poor biomarker for TMD and migraine.

The Vascular-Dependent and -Independent Actions of Calcitonin Gene-Related Peptide in Cardiovascular Disease.

The treatment of hypertension and heart failure remains a major challenge to healthcare providers. Despite therapeutic advances, heart failure affects more than 26 million people worldwide and is increasing in prevalence due to an ageing population. Similarly, despite an improvement in blood pressure management, largely due to pharmacological interventions, hypertension remains a silent killer. This is in part due to its ability to contribute to heart failure. Development of novel therapies will likely be at the forefront of future cardiovascular studies to address these unmet needs. Calcitonin gene-related peptide (CGRP) is a 37 amino acid potent vasodilator with positive-ionotropic and -chronotropic effects. It has been reported to have beneficial effects in hypertensive and heart failure patients. Interestingly, changes in plasma CGRP concentration in patients after myocardial infarction, heart failure, and in some forms of hypertension, also support a role for CGRP on hemodynamic functions. Rodent studies have played an important role thus far in delineating mechanisms involved in CGRP-induced cardioprotection. However, due to the short plasma half-life of CGRP, these well documented beneficial effects have often proven to be acute and transient. Recent development of longer lasting CGRP agonists may therefore offer a practical solution to investigating CGRP further in cardiovascular disease in vivo. Furthermore, pre-clinical murine studies have hinted at the prospect of cardioprotective mechanisms of CGRP which is independent of its hypotensive effect. Here, we discuss past and present evidence of vascular-dependent and -independent processes by which CGRP could protect the vasculature and myocardium against cardiovascular dysfunction.

Ischemic preconditioning protects against myocardial ischemia-reperfusion injury through inhibiting toll-like receptor 4/NF-κB signaling pathway in rats.

To investigate whether the protection of ischemic preconditioning (IPC) against myocardial ischemia/reperfusion (I/R) injury is mediated by toll-like receptor 4 (TLR4)/NF-κB pathway, and whether these effects are related to the release of calcitonin gene-related peptide (CGRP). Sprague-Dawley rats were subjected to 60 min of ligation of the left anterior descending coronary artery followed by 3 h of reperfusion to induce I/R injury. IPC was performed by 4 cycles of 3-min left coronary artery occlusion followed by 5-min reperfusion before the I/R. The expression of TLR4 mRNA was determined by RT-PCR. TLR4 and NF-κB protein expression were analyzed by immunohistochemistry. Myocardial infarct size, CGRP concentration in plasma and activity of creatine kinase in serum were also measured. IPC significantly reduced the infarct size and creatine kinase activity concomitantly with the increase in plasma CGRP concentration. The expressions of TLR4 protein and mRNA and NF-κB protein were increased by myocardial I/R injury, and dramatically inhibited by IPC. IPC protects against myocardial I/R injury by inhibition of TLR4/NF-κB pathway. These effects are related to the increased the release of CGRP.

Cetraxate raises levels of calcitonin gene-related peptide and substance P in human plasma.

Cetraxate hydrochloride (cetraxate), an anti-ulcer drug, produces a dose-related increase in mucosal blood flow. Recently, it was found that capsaicin-sensitive afferent nerves play an important role in gastric mucosal defence. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP) and substance P in the stomach. We studied the effect of cetraxate on human plasma CGRP and substance P in healthy subjects. Cetraxate (800 mg) or placebo were orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180 and 240 min after administration, followed by the extracting procedure, and submitted to a highly sensitive enzyme immunoassay system for CGRP and substance P. Single administration of cetraxate caused significant increases in plasma CGRP concentration at 60-120 min compared with placebo. Cetraxate significantly increased plasma substance P levels at 40-90 min compared with placebo. In this study, we hypothesized that cetraxate might indirectly stimulate capsaicin-sensitive afferent nerves and increase mucosal blood flow, and that this may be a key mechanism underlying its gastroprotective action.

Plasma calcitonin gene-related peptide concentration is comparable to control group among migraineurs and tension-type headache subjects during interictal period: response to comments by Tfelt-Hansen and Ashina

We thank Drs. Tfelt-Hansen and Ashina [1] for their interest in our article [2]. They have raised a valid point, namely that measurement units should be similar in the scientific literature. We assume that different units mentioned in previous studies were provided by the respective manufacturer of the kit, and we followed the same custom. However, in the interest of uniformity in the literature, as indicated by Drs. Tfelt-Hansen and Ashina, we provide revised results here (Table 1). A concern was raised regarding the higher inter-ictal concentration of plasma CGRP in the cubital blood than reported in previous studies [3–7]. The available literature provides conflicting results regarding plasma CGRP concentration in migraineurs, both ictal as well as inter-ictal, and even when the blood was collected from different areas (external jugular/internal jugular and cubital) [2–9]. Hence, no conclusion can be reached regarding the baseline concentration of CGRP in plasma. The higher concentration reported in the present study than in previous studies can be explained by a number of methodological factors. First, the CGRP has a very short half life, barely 7 min, hence we made sure that plasma samples were frozen to -70 C within 5 min of drawing the blood [10, 11]. In a number of studies the sample was centrifuged for 15 min [6, 8, 12]. This could have resulted in lower levels. Secondly, it must be remembered that peptides are unstable molecules and they need to be preserved at -70 C. At least in one study samples were stored at –20 C until analysis, and this could have affected the results [13]. Moreover, the plasma level of CGRP follows a circadian pattern and shows troughs and peaks, but at different times according to different studies [14, 15]. We had drawn blood samples between 9 a.m. and 12 noon, when CGRP concentration is highest [14]. Furthermore, sampling methods and anticoagulants may affect the quantitative analysis with some peptides [16]. These factors could have affected the results of previous studies as they used different anticoagulants, e.g. heparin or aprotinin [6, 8, 13]. We used EDTA tubes to collect the blood on the manufacturer’s recommendation. Lastly, the measurement of CGRP is influenced by a number of factors present in the plasma that may cross-react with it (Peninsula Lab Inc., LLC), hence we used the extraction-free kit. This further reduces the chances of error. The sensitivity of the ELISA kit used in this study was 21 pmol/l and the range was 0–6596 pmol/l (Peninsula Lab Inc., LLC) with intra-assay variation of less than 5%. Thus, the results of these kinds of studies warrant further studies in this area with better methodologies, until conclusive evidence is yielded. R. Gupta (&) Sleep and Headache Care, 1061 Kissan Marg, Barkat Nagar, Rajasthan, Jaipur 302015, India e-mail: guptaravi_2003@yahoo.co.in

Plasma calcitonin gene-related peptide concentration is comparable to control group among migraineurs and tension type headache subjects during inter-ictal period

Calcitonin gene-related peptide (CGRP) is known to increase during acute attack of migraine and tension type headache (TTH). However, its concentration during inter-ictal period is not known. This may help us to understand the pathophysiology of these headaches. The objectives of this study are to find out the concentration of CGRP in plasma during inter-ictal period among migraineurs and TTH and to compare it with control group through cross-sectional study from headache clinic of a tertiary centre. Study sample comprised of three groups: migraineurs, TTH subjects as well as a healthy control group. Fifty subjects in each group were included after screening for the respective inclusion criteria and exclusion criteria. None of the subjects was blood relatives of other subject. Their venous blood was drawn and plasma was separated to be kept at −70°C. CGRP was analysed with commercially available ELISA kit. Data were analysed with the help of SPSS V 11.0 for Windows. Chi-square, independent sample t test and one-way ANOVA with post hoc Tukey and univariate regression were performed. Plasma CGRP concentration was not different among three diagnostic groups (F = 0.78; P = 0.49). Similarly, plasma CGRP concentration was not different among episodic TTH and chronic TTH groups (t = 0.32; P = 0.97) and comparison of episodic and chronic migraine groups also revealed similar results in this study (1.14 vs. 0.94 ng/ml; P = 0.23). The presence of aura did not affect the inter-ictal CGRP levels among migraineurs (F = 0.16; P = 0.85). In conclusion, this study suggests that migraine and TTH could be episodic disorders and subjects have comparable CGRP levels during inter-ictal period.

Circulating calcitonin gene-related peptide and its placental origins in normotensive and preeclamptic pregnancies

The present study was designed to determine plasma calcitonin gene-related peptide concentration in both maternal and fetal circulations in normotensive and pre-eclamptic pregnancies and investigate whether placenta is 1 of its origins. Maternal blood, cord blood, and villous tissue were collected from women in normotensive pregnancies and complicated with pre-eclampsia. Calcitonin gene-related peptide concentrations were determined by radioimmunoassay. Cellular localizations of calcitonin gene-related peptide messenger ribonucleic acid and protein expressions in placental villi were determined by in situ hybridization and immunohistochemistry. The following results were reached: (1) maternal plasma calcitonin gene-related peptide concentrations increased with advancing gestation but fell after delivery; (2) both maternal and cord plasma calcitonin gene-related peptide concentrations were positively correlated with the infant birth weights; (3) compared with normotensive pregnancies, calcitonin gene-related peptide levels in both maternal and cord plasma decreased in pregnancies with pre-eclampsia; (4) in normotensive pregnancies, the plasma calcitonin gene-related peptide of the umbilical vein was higher than the umbilical artery, but no significant differences between vein and artery in pre-eclampsia; (5) calcitonin gene-related peptide messenger ribonucleic acid and protein were expressed by syncytiotrophoblast cells and villous vascular endothelial cells in normotensive pregnancies, but only weak or absent staining was observed in pre-eclamptic placentas; and (6) calcitonin gene-related peptide is secreted by villous tissue in explant culture in a time-dependent manner, but less calcitonin gene-related peptide was produced by villous tissues from patients with pre-eclampsia. Calcitonin gene-related peptide may play potential roles in maternal hemodynamic adaptation and fetal growth. Decreased circulating calcitonin gene-related peptide levels may be involved in maternal-fetal pathophysiology of pre-eclampsia. It is novel that placenta villous tissues might be one of the potential sources of calcitonin gene-related peptide during pregnancy.

Sumatriptan Causes Parallel Decrease in Plasma Calcitonin Gene-Related Peptide (CGRP) Concentration and Migraine Headache During Nitroglycerin Induced Migraine Attack

Sumatriptan-induced changes in plasma calcitonin gene-related peptide (CGRP) concentration and headache intensity were investigated in 19 female migraineurs during nitroglycerin-induced migraine attack. Sumatriptan nasal spray was administered 120 min after the onset of the attack. Blood samples were obtained immediately before and 60 min after sumatriptan administration. In those subjects whose migraine attack improved considerably 60 min after the treatment the plasma CGRP concentration decreased significantly (P<0.05). In contrast, plasma CGRP concentration failed to change in patients whose headache did not improve. In addition, plasma CGRP concentrations showed significant positive correlations with the headache scores both 60 and 120 min after sumatriptan administration (P<0.05). According to our results plasma CGRP concentration decreases parallel to headache intensity during sumatriptan treatment and this decrease in CGRP predicts effectiveness of antimigraine drug therapy. This supports that one of the main effects of triptans is to decrease CGRP release.

Correlation between CGRP and Migraine Attacks

Any hypothesis regarding pain in primary headache disorders rests on the classic observations which describe painful sensations as a result of mechanical or electrical stimulation of large cerebral arteries, venous sinuses, and dural arteries, by Ray and Wolff (1). These pain-sensitive supratentorial structures are supplied by nerve fibres that arise in the trigeminal ganglion. The fibres and the cell bodies contain a number of messengers but calcitonin gene-related peptide (CGRP) is the one most frequently expressed (2). A role of the trigemino-cerebrovascular system in the transmission of nociceptive information to the central nervous system is thus a viable proposition. Antidromic or local mechanical stimulation of sensory nerve endings results in vasodilation via the release of vasoactive materials such as CGRP. The cell bodies are located in the trigeminal ganglion, they send sensory fibres to various cranial structures, and connect to the CNS via the trigeminal nerve. In primary headaches, there is a clear association between the headache and the release of CGRP, but not with any of the other neuronal messengers. The background and current status have recently been reviewed in the journal (3). Several primary headaches, such as migraine, cluster and chronic paroxysmal hemicrania, are associated with increased levels of CGRP in the jugular vein during pain (3). Furthermore, CGRP in the antecubital vein increases by 25–30% during nitroglycerin-induced migraine attacks and the increase in CGRP correlates markedly with the headache intensity (4). In the present issue of the journal Juhasz and colleagues (5) demonstrate that sumatriptan decreases the plasma CGRP concentration in the antecubital vein during migraine attacks elicited by nitroglycerin administration. This decrease was present only in those patients whose headache showed parallel clinical improvement. In those patients whose headache did not improve, the CGRP concentrations failed to show a decrease after the administration of nasal sumatriptan. Furthermore, plasma CGRP significantly correlated with headache scores after sumatriptan treatment. These results underline the close relationship of CGRP release and migraine headache (6).

Comparison of the Effects of Cetraxate and its Major Metabolite on Human Plasma Gastrin, Somatostatin, Calcitonine Gene-Related Peptide and Substance P in Human Plasma

Cetraxate hydrochloride (cetraxate), an antiulcer drug, produces a dose related increase in mucosal blood flow. We have reported that cetraxate increases plasma calcitonin gene-related peptide (CGRP) and substance P in healthy human subjects (J. Pharm. Pharmacol., 56, p. 557, 2004). Cetraxate is rapidly metabolized to tranexamic acid in plasma. We investigated the effect of tranexamic acid on human plasma CGRP, substance P, gastrin and somatostatin. Tranexamic acid at a dose of 500 mg or placebo was orally administered in five healthy male volunteers. The blood samples were taken before and at 20, 40, 60, 90, 120, 180 and 240 min after administrations, followed by the extracting procedure, and submitted to the high sensitive enzyme immunoassay system for CGRP and substance P as previously developed. Single administration of tranexamic acid caused significant increases of plasma CGRP concentration at 60-90 min compared with placebo, but the level-time profile was a little different from that of cetraxate. Tranexamic acid had no significant effect on plasma gastrin, somatostatin and substance P levels compared with placebo. In this study, we thought that the gastroprotective effect of cetraxate might not be due to plasma metabolite, tranexamic acid, but direct stimulation of gastric mucosa.

MIGRAINE PATHOPHYSIOLOGY

MIGRAINE PATHOPHYSIOLOGY

NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly ( P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity ( P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly ( P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.

Studies on treating eczema by Chinese herbal medicine with anti-type IV allergic activity

To study Chinese herbal prescription for treatment of eczema based on the suppressive effect of Chinese herbal medicine on type IV allergic reaction. Various formulae composed of Chinese herbal medicines possessing suppressive effect on allergic contact dermatitis were formed based on the therapeutic principles of traditional Chinese medicine in treating eczema, and their effect on murine ear swelling, ear flake weight, dermal inflammatory infiltration cell count and plasma level of calcitonin gene related peptide (CGRP) were examined in mice with dinitrofluorobenzene induced dermatitis. A prescription, Composite Poria Decoction was formulated and made into granule form, which was used to treat 63 cases of eczema (atopic dermatitis was excluded), and compared with 59 cases treated with antihistamine that was aimed at the type I allergic reaction. Experimental study showed that all the 4 Chinese prescriptions had the effect of anti-type IV allergic reaction, among them, the formula for cooling blood, remove Heat, Wind and Dampness evil possessed the most potent effect in suppressing murine dermatitis, and it was also able to up-regulate the plasma CGRP concentration. The clinical cure rate of Composite Poria Granule treatment was 47.6%, and that of control was 22.0%, the difference was significant between the two groups (u = 2.9555, P < 0.01). Chinese herbal medicine has effect of anti-type IV allergic reaction. Composite Poria Granule has good effect in treating eczema.

Adaptation of Rainbow Trout to Seawater: Changes in Calcitonin Gene-Related Peptide Levels Are Associated with an Increase in Hormone–Receptor Interaction in Gill Membranes

Transfer of trout from freshwater to seawater produced changes in plasma calcitonin gene-related peptide (CGRP), calcitonin, and calcium levels. Three days after transfer, the plasma CGRP concentration increased from 517 ± 54 (n= 6) to 1874 ± 234 (n= 7) pg/ml. Ten hours after transfer, the plasma CT concentration in seawater-adapted trout was double the control value. Plasma calcium levels also changed: 2 days after transfer, the calcium increased 1.6-fold over the basal value. The increased plasma CGRP level was correlated with an increased specific binding of CGRP to its branchial membrane receptors. Scatchard analysis of the data revealed this increase to be mainly due to increased binding affinity, as there was no difference in binding capacity between control and transferred animals. Carbonic anhydrase activity in branchial membranes increased 2.2-fold over the control value 3 days after transfer. CGRP may thus play a role in osmoregulation and ionic balance.

The influence of salt intake on plasma calcitonin gene-related peptide in subjects with mild essential hypertension

Calcitonin gene-related peptide is a pleiotropic neuropeptide with potent vasodilatory properties, which interferes with renin release and might participate in cardiovascular homeostasis. We studied the influence of salt intake on the plasma concentration of calcitonin gene-related peptide, parathyroid hormone and on the renin-aldosterone system in 15 patients with mild hypertension. Each participant was studied after 1 week of high salt intake (200 mmol/day) and after 1 week of low salt intake (50 mmol/day). The order of the two diet periods was randomized and crossover. Plasma calcitonin gene-related peptide concentration was measured by radioimmunoassay after pre-extraction by reverse chromatography. Seven patients were classified as salt-sensitive and eight as salt-resistant. In the whole group the low salt intake caused a significant decrease in arterial pressure and the expected increase in plasma renin activity and in plasma aldosterone concentration. Such changes were accompanied by a significant increase in plasma calcitonin gene-related peptide. In salt-resistant patients in the sodium-replete state calcitonin gene-related peptide levels tended to be reduced in comparison with salt-sensitive patients. Sodium depletion, however, caused a more pronounced rise in plasma calcitonin gene-related peptide in salt-resistant hypertensives, who attained levels close to those in salt-sensitive hypertensives. Interestingly, in salt-resistant hypertensives changes in plasma calcitonin gene-related peptide were closely related to plasma renin activity (r = 0.71, P = 0.003), whereas no such correlation was found in salt-sensitive patients. Parathyroid hormone was not influenced by changes in salt intake. In subjects with mild hypertension calcitonin gene-related peptide is sensitive to changes in salt intake in the physiological range. Such a response seems to be linked to the individual arterial pressure response to salt, because salt-resistant patients showed reduced calcitonin gene-related peptide levels in the sodium-replete state and a more pronounced calcitonin gene-related peptide increase, closely related to plasma renin activity, during sodium deprivation.

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

Calcitonin Gene-Related Peptide: 24-Hour Profile and Responses to Volume Contraction and Expansion in Normal Men*

Plasma immunoreactive calcitonin-gene related peptide (CGRP) concentrations were measured in 10 normal male subjects, aged 23-34 yr, who were studied under 3 separate conditions at intervals of at least 1 week. In phase 1, plasma CGRP concentrations were measured hourly for 24 h during normal activity; in phase 2, the CGRP response to diuretic-induced volume depletion and upright posture was measured over 3 h; in phase 3, the CGRP response to volume loading and supine posture was measured over 4 h. During phase 1, the mean 24-h plasma CGRP concentration averaged 30 +/- 16 pmol/L; hourly CGRP concentrations ranged from 25-37 pmol/L over 24 h and oscillated from 16% below to 27% above the mean 24-h CGRP value, changes that were highly significant (P = 0.005). The peaks were at 0600 and 0700 h, while the nadirs were at 1200 and 2000 h. No significant difference was found between fasting CGRP at 0800 h and levels taken 1, 2, and 3 h postprandially (P = 0.68). During phase 2 (volume depletion and upright) mean plasma CGRP rose significantly, going from a baseline of 42 +/- 8 pmol/L at 0800 h to a peak of 60 +/- 10 pmol/L at 1100 h (P = 0.0005). The percent CGRP increment was relatively small (26% to 42%) compared to the rise in PRA (518% to 1033%) and aldosterone concentrations (333% to 465%). Hematocrit increased from 40.5 +/- 0.7% to 45.8 +/- 0.7% (P = 0.0001) in phase 2, while serum osmolality did not change significantly. In phase 3 (volume loading and supine), plasma CGRP did not change significantly, while PRA and aldosterone concentrations fell significantly (P = 0.0001); neither serum osmolality nor hematocrit changed significantly. We conclude that plasma CGRP concentrations fluctuate spontaneously and significantly during the day, and rise in response to volume depletion. The reasons for the CGRP fluctuations seen over 24 h, which are not apparent from this study, may be related to changes in vascular volume or other as yet unidentified factors. These studies are consistent with the concept that CGRP, acting either directly or through the renin-aldosterone system, may have a role in regulating peripheral vascular tone or controlling vascular volume.

Mechanism by which calcitonin gene-related peptide antagonizes insulin action in vivo

Calcitonin gene-related peptide (CGRP) is a peptide with structural homology to amylin, which is present in nerve terminals of skeletal muscle and intestine. The effect of this peptide on in vivo insulin action was studied in conscious rats. All rats received 180 min euglycemic (5.6 mM) insulin (21.5 pmol.kg-1.min-1) clamp study in combination with [3-3H]- and [U-14C]glucose infusions. In the basal state, the plasma CGRP concentration was 36 +/- 5 pM, and the skeletal muscle CGRP concentration was 376 +/- 88 pmol/kg wet wt. CGRP was infused at 100 pmol.kg-1.min-1 during the last 90 min of the insulin clamp study and determined a rise in plasma concentration to 781 +/- 34 pM. Hepatic glucose production was stimulated by the infusion of CGRP (35.6 +/- 6.1 vs. 24.4 +/- 4.4 mumol.kg-1.min-1). During infusion in insulin alone, glucose uptake was 133.3 +/- 8.9 mumol.kg-1.min-1 and decreased to 105.5 +/- 12.2 mumol.kg-1.min-1 with CGRP. However, the whole body rates of glycolysis (3H2O generation) were higher during the infusion of CGRP (83.9 +/- 6.1 mumol.kg-1.min-1) compared with insulin alone (72.2 +/- 7.8 mumol.kg-1.min-1). By contrast, CGRP determined a severe impairment in muscle glycogen synthesis (11.7 +/- 3.9 vs. 47.8 +/- 5.0 mumol.kg-1.min-1). Skeletal muscle glucose 6-phosphate concentration was significantly increased after CGRP infusion compared with insulin alone (0.540 +/- 0.052 vs. 0.219 +/- 0.038 mumol/g wet wt; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)